This Program has provided compelling evidence for a self amplifying cycle of interactions between neurons and glia, mediated largely by neuroinflammatory cytokines acting as drivers of Alzheimer's disease (AD) pathogenesis; chief among these is interleukin-1 (IL-1). We have focused on the entry points into this cycle, which is to say the early events in a given neuron's circuit of interactions with its local environs. Recent examinations of human tissue and of a newly acquired transgenic Alzheimer model indicate that pathology of the Alzheimer type is initially associated with neuronal elevation of apolipoprotein E (ApoE) and -amyloid precursor protein (APP). Empirical studies in cell culture suggest that the APP/ApoE response in tissue is due to a causal relationship in which APP expression is dependent on co-expression of ApoE, with ApoE e3 more efficacious than ApoE e4, and is modulated by IL-1. Neuronal APP elevation is accompanied by secretion of APP fragments, which activate microglia and cause glutamate release. Together, this suggests that a glutamate-ApoE-APP axis is initialized in the early neuronal responses to adverse stimuli and neuroinflammation. With these results, we were surprised to find that i) APP expression declines in neuronal somata as one approaches mature A plaques, either temporally or spatially; and ii) glial activation persists in Alzheimer brain in the presence or following clearance of A plaques. Together, these data inspire a hypothesis that unifies the current renewal of this Program: The typical acute-phase response of neurons to adverse stimuli is to elevate ApoE and APP expression via a coordinated, causal relationship between ApoE and APP expression that becomes uncoupled in AD pathogenesis, leaving neurons with insufficient APP and a propensity to make inappropriate cellular responses and to succumb to the excitotoxic stress perpetrated by classical activation of microglia. Human tissue and model systems will be used in Project 1 to identify and elucidate the basic elements of the glutamate-ApoE-APP axis, and the role of IL-1 in its failure in AD. Project 2 will identify, in two unique populations, common pathways for microglial activation and cytokine release and the degree to which this activation is reflected in mRNA and protein expression profiles. Project 3 will investigate key aspects of microglial activation related to oxidative production of glutamate and the differential modulation of this activation by IL-1a gene polymorphisms. Three cores provide administrative coordination (Core A), tissue banking and processing (Core B), and molecular/biochemical sample analyses (Core C) for these studies. The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD.